Biophysics of Temporal Interference Stimulation.

Temporal interference (TI) is a non-invasive neurostimulation technique that utilizes high-frequency external electric fields to stimulate deep neuronal structures without affecting superficial, off-target structures. TI represents a potential breakthrough for treating conditions, such as Parkinson's disease and chronic pain. However, early clinical work on TI stimulation was met with mixed outcomes challenging its fundamental mechanisms and applications. Here, we apply established physics to study the mechanisms of TI with the goal of optimizing it for clinical use. We argue that TI stimulation cannot work via passive membrane filtering, as previously hypothesized. Instead, TI stimulation requires an ion-channel mediated signal rectification process. Unfortunately, this mechanism is also responsible for high-frequency conduction block in off-target tissues, thus challenging clinical applications of TI. In consequence, we propose a set of experimental controls that should be performed in future experiments to refine our understanding and practice of TI stimulation. A record of this paper's transparent peer review process is included in the Supplemental Information.